Cocaine remains a major public health concern due to the continued high level of emergency room admissions involving cocaine use. Cardiovascular complications represent a large proportion of these admissions. Recent research has focused on determining whether proposed treatment agents will alter the cardiovascular effects of cocaine in conscious squirrel monkeys. Although not planned, it is likely that some individuals will use a treatment agent in combination with cocaine. Squirrel monkeys were seated in standard restraint chairs and placed in sound attenuating chambers 5 days per week. Twice per week the monkeys were administered cocaine, a treatment agent, or the two in combination about 30 min into the session. Cardiovascular parameters were monitored for an additional 60 min. In conscious squirrel monkeys cocaine produces clear increases in BP and HR. Drugs that interact with dopamine have been tested for cardiovascular effects both alone and in combination with cocaine. GBR 12909, a selective dopamine uptake inhibitor, produced small increases in blood pressure and heart rate, but when given in combination with cocaine, no potentiation of the cocaine effect was observed. Similarly, the dopamine D1 agonist SKF 82958 produces increases in blood pressure and heart rate, but did not potentiate cocaine's effects at the doses tested. The partial D1 agonist SKF 77434 did not increase blood pressure and heart rate when given alone, and appeared to attenuate the effects of cocaine. The dopamine D2 agonist quinpirole increased heart rate and decreased blood pressure. When given in combination with cocaine, sub-additive effects were observed. In contrast, the dopamine autoreceptor/D3 antagonist UH 232 produced increases in blood pressure and heart, and when given in combination with cocaine additive effects are observed. No significant effects on ECG were observed for any of the drugs. Therefore, of the drugs tested thus far, only UH 232 would appear to represent a significant risk when used in combination with cocaine. The contribution of the metabolites of cocaine to its cardiovascular effects is of interest as complications to cocaine use have been reported hours after administration. Further, cocaine is often used repeatedly for many hours, so metabolite concentrations can be elevated. This was studied in squirrel monkeys by the systemic administration of various cocaine metabolites. Neither benzoylecgonine nor ecgonine methyl ester produced significant cardiovascular effects. The minor metabolite norcocaine produced increases in blood pressure, but only at doses higher than cocaine and the effects where relatively brief. In contrast, cocaethylene, a metabolite produced when alcohol is co-administered with cocaine, produced cardiovascular effects with potency similar to cocaine. These results suggest that the metabolites of cocaine do not contribute to its overall cardiovascular effect, with the possible exception of cocaethylene.